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1.
Cancer Genet ; 237: 90-96, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31447071

RESUMO

PURPOSE: Multiple lines of evidence have suggested a likely causative role in breast/ovarian cancer (BrCa/OvCa) predisposition for the BRCA1 p.(Val1833Met) variant, predominantly found among Greek patients. Our aim was to study the variant's prevalence and founder effect on the Greek population, while providing additional data for its pathogenicity. METHODS: We genotyped 3531 BrCa/OvCa patients using Sanger and next generation sequencing, as well as 1558 healthy, age-matched females with real-time PCR. Carriers underwent haplotype analysis to determine a founder effect. A co-segregation analysis was applied to estimate the likelihood ratio for pathogenicity. RESULTS: In total, 27 BrCa/OvCa patients (0.77%; 27/3531) were found to carry the p.(Val1833Met) variant. No carriers were identified in the control group diagnosis. A common shared haplotype, spanning 2.76 Mb on chromosome 17 was demonstrated among carriers, establishing the founder effect. BRCA1, p.(Val1833Met) is possibly a disease-associated variant, supported by a likelihood ratio of 1.88, while a correlation to ovarian cancer is suspected. CONCLUSIONS: Altogether, BRCA1, p.(Val1833Met) variant is a Greek founder and is very likely to predispose for BrCa/OvCa. Therefore, such carriers should be counselled accordingly, with clinical recommendations supporting surveillance and risk-reduction strategies, while providing the option for targeted therapeutic interventions.

2.
J Med Genet ; 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300551

RESUMO

BACKGROUND: Gene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations. METHODS: To further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case-control analysis. RESULTS: Herein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively. CONCLUSION: Studying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

3.
Hum Mutat ; 40(11): e1-e23, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31209999

RESUMO

BRCA1 BRCA2 mutational spectrum in the Middle East, North Africa, and Southern Europe is not well characterized. The unique history and cultural practices characterizing these regions, often involving consanguinity and inbreeding, plausibly led to the accumulation of population-specific founder pathogenic sequence variants (PSVs). To determine recurring BRCA PSVs in these locales, a search in PUBMED, EMBASE, BIC, and CIMBA was carried out combined with outreach to researchers from the relevant countries for unpublished data. We identified 232 PSVs in BRCA1 and 239 in BRCA2 in 25 of 33 countries surveyed. Common PSVs that were detected in four or more countries were c.5266dup (p.Gln1756Profs), c.181T>G (p.Cys61Gly), c.68_69del (p.Glu23Valfs), c.5030_5033del (p.Thr1677Ilefs), c.4327C>T (p.Arg1443Ter), c.5251C>T (p.Arg1751Ter), c.1016dup (p.Val340Glyfs), c.3700_3704del (p.Val1234Glnfs), c.4065_4068del (p.Asn1355Lysfs), c.1504_1508del (p.Leu502Alafs), c.843_846del (p.Ser282Tyrfs), c.798_799del (p.Ser267Lysfs), and c.3607C>T (p.Arg1203Ter) in BRCA1 and c.2808_2811del (p.Ala938Profs), c.5722_5723del (p.Leu1908Argfs), c.9097dup (p.Thr3033Asnfs), c.1310_1313del (p. p.Lys437Ilefs), and c.5946del (p.Ser1982Argfs) for BRCA2. Notably, some mutations (e.g., p.Asn257Lysfs (c.771_775del)) were observed in unrelated populations. Thus, seemingly genotyping recurring BRCA PSVs in specific populations may provide first pass BRCA genotyping platform.

4.
J Hum Genet ; 64(8): 767-773, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31089269

RESUMO

PALB2 loss-of-function variants play an important role in breast, pancreatic and possibly, ovarian and gastric cancer susceptibility. Their frequency can be influenced by founder effects, already described in some populations. Herein, we have assessed the possible founder effect of PALB2 c.2257C>T (p.Arg753*) truncating variant among Greek breast cancer patients, while investigating possible correlations with cancer diagnoses. Following a lead deriving from a background study of highly selected Greek breast cancer patients, a total of 2496 breast and 697 ovarian cancer patients were directly genotyped for the PALB2 c.2257C>T truncating variant. Consequently, haplotype analysis was conducted on identified carriers, using seven microsatellite markers. The prevalence of the PALB2 variant was 0.24% (6/2496) and 0.14% (1/697) among breast and ovarian cases, respectively. Family history seems to be an important factor for the variant identification, although not reaching statistical significance. Microsatellite analysis on 12 carriers revealed a common shared haplotype, spanning a chromosomal region of ~1.2 Mb; the variant was possibly introduced in the Greek population ~1600 years ago. The variant confers high breast cancer risk, as illustrated by comparison with publicly available control groups. Genetic testing for PALB2, especially for the Greek founder c.2257C>T truncating variant, should be seriously considered in Greek breast cancer cases, since such findings could assist appropriate clinical management for the patients and their families.

6.
Hum Mutat ; 40(5): 631-648, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30851065

RESUMO

Genetic testing for cancer predisposition leads to the identification of a number of variants with uncertain significance. To some extent, variants of BRCA1/2 have been classified, in contrast to variants of other genes. CHEK2 is a typical example, in which a large number of variants of unknown clinical significance were identified and still remained unclassified. Herein, the CHEK2 variant assessment was performed through an in vivo, yeast-based, functional assay. In total, 120 germline CHEK2 missense variants, distributed along the protein sequence, and two large in-frame deletions were tested, originating from genetic test results in breast cancer families, or selected from the ClinVar database. Of these, 32 missense and two in-frame deletions behaved as non-functional, 73 as functional, and 15 as semi-functional, after comparing growth rates of each strain with positive and negative controls. The majority of non-functional variants were localized in the CHK2 kinase and forkhead-associated domains. In vivo results from the non-functional variants were in agreement with in silico predictions, and, where available, with strong breast cancer family history, to a great extent. The results of the largest, to date, yeast-based assay, evaluating CHEK2 variants, can complement and assist in the classification of rare CHEK2 variants with unclear clinical significance.

7.
Gynecol Oncol ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30446274

RESUMO

BACKGROUND: Tissue genomic heterogeneity (t-HET) in patients with epithelial ovarian cancer (OVCA) is related to tissue plasticity, i.e., flexibility to adapt to adverse molecular environments. Here, we interrogated the presence and clinical relevance of OVCA t-HET. METHODS: We applied high-depth (>2000×) sequencing on 297 paraffin tissue samples (fallopian tubes, ovaries, intra-abdominal metastases) from 71 treatment-naïve patients who subsequently received first-line platinum-based chemotherapy. Based on tissue mutation patterns, we distinguished tissue genotypes into: no mutation (33/297 samples; 11.1%), stable (173; 58.2%) and unstable (91; 30.7%). We profiled genotypes per patient and assessed t-HET in 69 patients. Predicted pathogenic mutations refer to germline and/or tissues. RESULTS: Among all 71 patients, 46 (64.8%) had pathogenic BRCA1 mutations and 15 (21.7%) had BRCA1/2 disruption (i.e., pathogenic mutations with position-LOH). We classified 29 patients with t-HET (42%), all with pathogenic BRCA1; t-HET was observed in 64% with such mutations (p < 0.001). As opposed to non-t-HET, matched tissues in t-HET shared pathogenic BRCA1 (p < 0.001) but not BRCA2 and TP53. Germline BRCA1 mutations in tissues exhibited position-LOH; heterozygous status; or, partial loss of the inherited allele accompanied by additional clonal mutations. Patients with t-HET had worse outcome (log-rank p = 0.048 [progression-free]; p = 0.037 [overall survival]), including 12/15 patients with disrupted BRCA1/2 and 3 BRCA1 carriers with partial germline loss in tissues. CONCLUSIONS: Pathogenic BRCA1 mutations appear necessary but may not be sufficient for the establishment of t-HET. t-HET may be associated with worse outcome, including in patients with disrupted BRCA1/2, which is usually considered as a favourable marker. OVCA t-HET may need to be addressed for treatment decisions.

8.
Case Rep Surg ; 2018: 6895974, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30327742

RESUMO

We describe an asymptomatic case of PJS in a six-year-old boy with café au lait spots in several parts of his body, a large gastroduodenal polyp, two polyps near the ampulla of Vater, and another in the jejunum. This patient shows some unique aspects of PJS. No other such large gastric polyp in a Peutz-Jeghers child is reported in the literature. The large size of the gastric polyp with lack of symptoms is unusual and poses a unique challenge in terms of management and surgical resection.

10.
J Natl Cancer Inst ; 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30099541

RESUMO

Background: Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor-negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. Methods: Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium (TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. Results: Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants. Conclusions: Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.

11.
J Hum Genet ; 63(11): 1149-1158, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30111881

RESUMO

RAD51D gene's protein product is known to be involved in the DNA repair mechanism by homologous recombination. RAD51D germline mutations have been recently associated with ovarian and breast cancer (OC and BC, respectively) predisposition. Our aim was to evaluate the frequency of hereditary RAD51D mutations in Greek patients. To address this, we have screened for RAD51D germline mutations 609 BRCA1- and BRCA2-negative patients diagnosed with OC, unselected for age or family history, and 569 BC patients diagnosed under 55 years and with an additional relative with BC or OC. We identified four pathogenic mutations in four unrelated individuals with family history of BC and/or OC. Three of the RAD51D carriers had developed BC, while the other one was an OC patient, thus accounting for a mutation frequency of 0.16% in the OC cohort and 0.53% in the BC cohort. One of the detected mutations is novel (c.738 + 1G > A), whereas the rest had been detected previously (p.Gln151Ter, p.Arg186Ter, and p.Arg300Ter). It is noteworthy that the 4 carrier families had 13 BC cases and only 4 OC cases. Our data support that RAD51D should be implemented into the comprehensive multigene panel, as mutation carriers may benefit from the administration of PARP inhibitors.

12.
Am J Hum Genet ; 103(1): 3-18, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29909963

RESUMO

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

13.
J Hum Genet ; 63(8): 877-886, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29785007

RESUMO

Germline CHEK2 mutations confer increased cancer risk, for breast and other types, which is variable depending on the specific mutation. Of these, Large Genomic Rearrangements (LGRs) have been rarely reported; to date only eight LGRs have been published with just the Czech founder mutation, the deletion of exons 9 and 10, being molecularly characterized and studied extensively. The present study aimed to molecularly define and determine the contribution of two rare, apparently novel CHEK2 LGRs, among Greek breast cancer patients. These specifically involve a ~6 kb in-frame deletion of exons 2 & 3 that removes CHEK2's FHA domain and a ~7.5 kb in-frame deletion of exon 6, which removes an α-helix of CHEK2's kinase domain. The latter was identified in 5 out of 2355 (0.22%) patients tested, while haplotype analysis revealed a common disease-associated haplotype, suggesting a single common ancestor and a Greek founder. Although in-frame, this LGR is predicted to be damaging by a yeast-based functional assay and structure-function predictions. The present study highlights the existence of rare, population-specific, genomic events in a known breast cancer predisposing gene, which can explain a proportion of hereditary breast cancer. Identification of such mutation carriers is rather important since appropriate clinical actionability will be inferred.


Assuntos
Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Deleção de Genes , Predisposição Genética para Doença , Adulto , Idoso , Neoplasias da Mama/patologia , Simulação por Computador , Análise Mutacional de DNA , Feminino , Rearranjo Gênico , Grécia , Haplótipos/genética , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Saccharomyces cerevisiae/metabolismo , Relação Estrutura-Atividade , Adulto Jovem
14.
Cancer Genet ; 220: 19-23, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29310834

RESUMO

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder caused by germline mutations in the STK11 tumor suppressor gene. PJS patients face a cumulative cancer risk as high as 93% for all sites combined. The present study reports the spectrum of STK11 mutations in eight families with clinical diagnosis of PJS, summarizes the clinical characteristics of sixteen mutation carriers and launches a National Registry for PJS in Greece. STK11 loss-of-function (LoF) mutations were detected in 87.5% of index patients. Carriers presented with their first manifestation at a median age of 24.9 years, while early-onset breast cancer was the most frequent malignancy observed, highlighting the need for breast surveillance. Out of the deleterious STK11 mutations identified, two were novel: c.375_376delGT and c.676_679dupAACG, with 57.2% of these potentially occurring de novo. Using all available clinical and genetic data, the National Registry for Greek PJS was established in an attempt to better characterize the syndrome and raise awareness among patients and clinicians (available at https://www.peutzjeghersgreece.org). This is the first comprehensive genetic analysis and clinical characterization of Greek PJS patients, where a high incidence of breast cancer was observed and the first attempt to centralize all data in a National Registry.

15.
Breast Cancer Res Treat ; 169(1): 105-113, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29335925

RESUMO

PURPOSE: Male breast cancer (MBC) is a rare cancer entity, with mutations in BRCA1 and BRCA2 genes accounting for ~ 10% of patients. Multiple-gene sequencing has already entered clinical practice for female breast cancer, whereas the performance of panel testing in MBC has not been studied extensively. Therefore, the aim of this study was to evaluate the clinical utility of panel testing for MBC, by the largest gene panel used so far, through investigation of patients deriving from a population with known founder effects. METHODS: Genomic DNA from one hundred and two Greek MBC patients, unselected for age and family history, was used to prepare libraries which capture the entire coding regions of 94 cancer genes. RESULTS: Loss-of-function (LoF) mutations were found in 12.7% of the cases, distributed in six genes: BRCA2, ATM, BRCA1, CHEK2, PMS2, and FANCL. BRCA2 mutations were the most frequent, followed by ATM mutations, accounting for 6.9 and 2%, respectively, while mutations in other genes were detected in single cases. Age at diagnosis or family history was not predictive of mutation status. Beyond mutations in established breast cancer predisposing genes, LoF mutations in PMS2 and FANCL among MBC patients are reported here for the first time. CONCLUSIONS: Our findings, using the largest gene panel for MBC patients so far, indicate that BRCA testing should be the primary concern for MBC patients. Until sufficient evidence arises from larger studies, multiple-gene panels may be of limited benefit for MBC and their families, at least for MBC patients of specific descent.

16.
Sci Rep ; 7(1): 16697, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29196670

RESUMO

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder causing benign tumors in the brain and other vital organs. The genes implicated in disease development are TSC1 and TSC2. Here, we have performed mutational analysis followed by a genotype-phenotype correlation study based on the clinical characteristics of the affected individuals. Twenty unrelated probands or families from Greece have been analyzed, of whom 13 had definite TSC, whereas another 7 had a possible TSC diagnosis. Using direct sequencing, we have identified pathogenic mutations in 13 patients/families (6 in TSC1 and 7 in TSC2), 5 of which were novel. The mutation identification rate for patients with definite TSC was 85%, but only 29% for the ones with a possible TSC diagnosis. Multiplex ligation-dependent probe amplification (MLPA) did not reveal any genomic rearrangements in TSC1 and TSC2 in the samples with no mutations identified. In general, TSC2 disease was more severe than TSC1, with more subependymal giant cell astrocytomas and angiomyolipomas, higher incidence of pharmacoresistant epileptic seizures, and more severe neuropsychiatric disorders. To our knowledge, this is the first comprehensive TSC1 and TSC2 mutational analysis carried out in TSC patients in Greece.

18.
J Clin Oncol ; 35(20): 2240-2250, 2017 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-28448241

RESUMO

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.


Assuntos
Neoplasias da Mama Masculina/genética , Genes BRCA1 , Genes BRCA2 , Herança Multifatorial , Mutação , Neoplasias da Próstata/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Predisposição Genética para Doença , Testes Genéticos , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos
19.
Am J Cancer Res ; 7(1): 98-114, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28123851

RESUMO

The preservation of pathogenic BRCA1/2 germline mutations in tumor tissues is usually not questioned, while it remains unknown whether these interact with somatic genotypes for patient outcome. Herein we compared germline and tumor genotypes in operable triple-negative breast cancer (TNBC) and evaluated their combined effects on prognosis. We analyzed baseline germline and primary tumor genotype data obtained by Sanger and Next Generation Sequencing in 194 TNBC patients. We also performed multiple tests interrogating the preservation of germline mutations in matched tumors and breast tissue from carriers with available material. Patients had been treated within clinical trials with adjuvant anthracyclines-taxanes based chemotherapy. We identified 50 (26%) germline mutation carriers (78% in BRCA1) and 136 (71%) tumors with somatic mutations (83% in TP53). Tumor mutation patterns differed between carriers and non-carriers (P<0.001); PIK3CA mutations were exclusively present in non-carriers (P=0.007). Germline BRCA1/2 mutations were not detected in matched tumors and breast tissues from 14 out of 33 (42%) evaluable carriers. Microsatellite markers revealed tumor loss of the germline mutant allele in one case only. Tumors that had lost the germline mutation demonstrated a higher incidence of somatic TP53 mutations as compared to tumors with preserved germline mutations (P=0.036). Germline mutation status significantly interacted with tumor TP53 mutations for patient disease-free survival (interaction P=0.026): In non-carriers, tumor TP53 mutations did not affect outcome; In carriers, those with mutated TP53 tumors experienced more relapses compared to those with wild-type TP53 tumors (36% vs. 9% relapse rate, respectively). In conclusion, we show that loss of germline BRCA1/2 mutations is not a rare event in TNBC. This finding, the observed differences in tumor genotypes with respect to germline status and the prognostic interaction between germline BRCA1-related and tumor TP53 mutation status prompt for combined germline and tumor genotyping for the classification of TNBC, particularly in the context of clinical trials evaluating synthetic lethality drugs.

20.
Breast Cancer Res Treat ; 161(1): 117-134, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27796716

RESUMO

PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.


Assuntos
Alelos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Biomarcadores Tumorais , Cromossomos Humanos Par 11 , Feminino , Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Humanos , Locos de Características Quantitativas , Risco
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